Physical Sciences Inc. (PSI) proposes to combine new and existing retinal imaging technologies to yield powerful new dye-free, functional imaging capabilities to ocular blood flow. We have previously demonstrated a new technique called tracking Doppler flowmetry (TDF) for the acquisition of wide-field, high dynamic range Doppler frequency-resolved maps of the retina. In this manner, blood flow information can be displayed and quantified with novel binning, color encoding, and equalization techniques for eyes with diseases such as age-related macular degeneration, or in response to factors affecting neuronal or metabolic activity (light stimulation, exercise, or pharmaceutical agent). The long confocal range gate of TDF is at once beneficial, providing high flow sensitivity and contrast due to inclusion of multiple-scattering events, large scattering receive angle, and low sensitivity to input beam angle within a long interaction range, and detrimental in terms of axial localization of flow. Optical Doppler tomography, conversely, has a narrow coherence range gate that provides high axial flow discrimination but is sensitive only to single-scattering with axial velocity components in a narrow acceptance angle. In the proposed program, we will develop 2 methods for improved axially discrimination with TDF: stereoscopic operation and hybridization with swept sources using the principles of Fourier domain optical coherence tomography. Advanced data processing algorithms will also be implemented. The improved system will be tested in human volunteers to 1) demonstrate quantifiable and reproducible depth-resolved retinal Doppler blood flow mapping; 2) measure blood flow changes in relation to visual stimulus-evoked neuro-vascular coupling mechanisms; and 3) enable detailed pulsatile flow phase portraits across a range of vessel sizes and flow velocity by synchronization to the cardiac cycle. This work will provide a valuable diagnostic tool to clinicians and researchers for the study of retinal function and the mechanisms and treatment of eye disease. Relevance of this research to public health: The retina is 1 of the most highly vascularized tissues in the body and is also most susceptible to damage from deficits in blood flow. Many degenerative and angiogenerative diseases of the eye, such as age-related macular degeneration and diabetic retinopathy, have either hemodynamic consequences or causes, though many of the mechanisms remain unknown or obscure. Development of better diagnostic tools will lead to increased understanding of the contribution of vascular blood flow and capillary perfusion to the inception and progression of retinal diseases, and also to research on visual signal transduction, higher order brain processing and modulation, and the study of advanced therapeutic interactions and pharmaceutical effects. [unreadable] [unreadable]